Prevalence of celiac disease in Iranian patients with rheumatologic disorders.

Aim: Patients with Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Fibromyalgia (FM) may have underlying non-diagnosed celiac disease (CD). Background: The aim of this study was to determine the prevalence of CD in patients with these underlying diseases in Iran. Methods: This cross-sectional study was performed among 300 consecutive patients with SLE, RA, and FM (each group 100 patients) since 2015 to 2017. The blood samples were collected and serum IgA anti-tissue trans-glutaminase (Anti-tTG) level was assessed for all patients. The seropositive patients underwent endoscopy and duodenal/jejunal biopsy according to the Marsh classification. Results: Out of 300 investigated patients with mean age of 41.2 years old, 92% of patients with SLE, RA and fibromyalgia were women. Among 100 patients with SLE, only 1 subject (1%), out of 100 patients with RA 3 subjects (3%), and none of the patients with fibromyalgia were seropositive for CD (with overall prevalence 1.4). All four patients were female and categorized as Marsh III. Conclusion: The results of the study indicated that patients with lupus have the same prevalence, but subjects with RA had three times higher prevalence rate than normal population for CD. Therefore, CD investigation in these individuals can improve their quality of life.


Introduction
1 Celiac disease (CD) is a lifetime gluten-induced autoimmune disease of small intestine affecting vulnerable individuals with worldwide and local prevalence rate of one and three percent, respectively. The diagnosis is based on serological antibodies and positive biopsy upon gluten-containing diet (1). The role of gastrointestinal factors in rheumatologic diseases, was firstly described by Smith in early 1920s There are multiple HLA and non HLA genes which are the same for celiac and rheumatologic diseases (17). Some incomplete atypical rheumatologic diseases forms are related to Gliadin activity (18). Among the other etiological factors for association of CD and SLE, ultraviolet exposure and hypovitaminosis-D are common predisposing factors (19)(20)(21)(22)(23)(24)(25). Few studies have previously investigated the association between RA and CD in Iran, but we did not find any documents regarding this association with SLE and FM in the literature. Therefore, the aim of this study was to assess the prevalence of celiac in patients with SLE, RA, and FM in Iranian population.

Methods
In this cross-sectional study, 300 patients with SLE, RA, and FM (each group compromise 100 patients) referred to Labbafinejad Hospital from 2015 to 2017 were enrolled. Inclusion criteria were presence of SLE, RA or FM and exclusion criteria were known history of gastrointestinal disease or surgery. Diagnosis criteria were made by rheumatologist according to ACR criteria. A patient satisfied diagnostic criteria for FM if the following 3 conditions were met; widespread pain index; symptoms had been present at a similar level for at least 3 months; the patient had no disorder that would otherwise explain the pain. All patients were assessed by clinical examination and medical history taking. 5 ml blood samples were collected and the level of Anti-tTG IgA (PharmaChimi, Iran) and serum IgA (Parsazmon, Iran) were assessed by ELISA kit and Immunoturbidimetry, respectively, according the manufacture instructions. Patients with IgA deficiency in the population studied were excluded using Anti-tTG IgG. The informed consent form was attained from all participating patients for blood sampling and Helsinki Declaration was respected all over the study. The study was approved by ethic committee of Research institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
A seropositive patient who had tTG-IgA more than 10 IU/ml in ELISA test underwent endoscopy and also duodenal/jejunal biopsy (3 to 4 samples) for histological assessment according to the Marsh classification. The patients showing villous atrophy consistent with CD diagnosis underwent gluten-free regimen and after six months were rechecked for therapeutic response. Data were collected by checklist including demographic, clinical, and laboratory results.
Data analysis was performed by SPSS (version 20.0) software [Statistical Procedures for Social Sciences; Chicago, Illinois, USA]. Chi-Square, Fisher, and ANOVA tests were used and were considered statistically significant at P values less than 0.05.
Among patients with SLE, only 1 subject (1%), among RA patients, 3 subjects (3%), and none of the patients with FM were seropositive for CD (with overall prevalence 1.4). IgA deficiency was not reported in any cases. All seropositive cases underwent endoscopy and histopathological evaluation confirmed CD diagnosis in all of them. The histological examinations showed that all CD patients were female and categorized as Marsh III. After 6 months GFD, the serological marker was backed to normal in all CD patients.
The distribution of clinical symptoms across the groups is shown in table 2. Musculoskeletal pain was the most predominant symptom in all studied groups (SLE: 39%; FM: 63% and RA: 37%). Also nausea/vomiting 22(22%) and gas passing 17(17%) in SLE patients, depression 53(53%) and GERD 36(36%) in FM and nausea/vomiting 29(29%) and anxiety 19(19%) in RA was the more frequent symptoms. The common symptoms in CD patients was musculoskeletal pain and belching.

Discussion
In current study the prevalence of CD in patients with SLE, RA, and FM was assessed and the result showed that the frequency of CD in Iranian patients with rheumatologic disorders is 1.4% (four CD patients including three with RA and one with SLE). In a review study in Iran, Rostami Nejad et al. (25) reported that the prevalence of this disease in general population in different parts of the country is between 0.5 and 1 percent which is similar to European and United States studies (17,18). Nutritional factors may have an effect on the relationship between CD and SLE. Studies have shown that people with CD are at higher risk for SLE than the general population, but the absolute risk is low (4). Freeman (4) reported that among 264 celiac patients, six (2.4%) had SLE in follow-up. On the other hands, Catassi et al. (23) showed that all 24 seropositive out of 103 SLE patients were negative in pathological assessment for CD. Shani et al. (6) reported that CD was significantly more common in SLE patients with a rate of 0.8% versus 0.2% compare with healthy subjects. Similar to Shani et al. study, we found that the prevalence of CD in SLE patients was 1% (CI95%: 0.1 to 1.2). Ben-Abdelghani et al. (24) found that among 24 SLE patients, 8% had positive anti-tTG antibody but only one patient was approved by pathological assessment. However, according to Freeman study longer follow-up would results in higher prevalence rate (4). Gluten-free diet had a direct impact on patients' quality of life with FM syndrome that had CD at the same time. Rodrigo et al. (8,10) reported 6.7% rate for CD in FM patients who all were Marsh III and had therapeutic response to gluten-free regimen. In the other hand, in accordance to our finding, Tovoli et al. (9) reported no association between FM and CD. The previous studies indicated that the possible causes of CD in RA are HLA predisposing role, immunological etiologies, family-clustering, geographic factor effects, and nutritional predisposition. In contrast with our findings, Moghtaderi et al. (12) did not find any cases of CD among patients with RA. James et al. (28) reported only one case of CD among 160 RA patients with pathology confirmation. Differently for our results, Coaccioli et al. (13) reported no celiac case in RA patients versus 0.5 to 1 percent in general population (29). The prevalence rate of CD in RA patients in our study was 3% (CI 95% 0.2 to 3.2) which is 3 times higher than general population. This prevalence is quite higher than previously reported (13,28). In line with Rodrigo et al. (8) all our patients were in Marsh III stage. In conclusion, the results of the study indicated that patients with SLE have the same prevalence, but patients with RA have three times higher prevalence rate than normal population for CD. Therefore, the investigation of larger sample size with follow-up would be beneficial to attain more definite results and can improve the patient's quality of life.

Conflict of interests
The authors declare that they have no conflict of interest.   (19)  44(44)  14(14) Anxiety